General (including evidence of efficacy)

Residual cardiac risk with mixed dyslipidemia

An elevated level of low density lipoprotein cholesterol (LDL-C) is established as a risk factor for the development of coronary and peripheral atherosclerotic vascular disease. Numerous randomized, prospective trials using 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have demonstrated the ability of these agents to reduce LDL-C and lower cardiovascular morbidity and mortality.

On average, a reduction of 25% to 35% in LDL-C with statin therapy has been associated with a 25% to 30% reduction in cardiovascular events, including myocardial infarction, ischemic stroke, and death. Additionally, trials using high dose statins have shown greater LDL-C reduction and incremental improvement in cardiovascular events as compared to moderate dose statins. Based upon multiple lines of evidence, the most recent iteration of the American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol continues to recommend the use of statins as the initial and primary therapy for the treatment of dyslipidemia.

Despite guideline recommendations and the aggressive use of high-dose statin therapy in high risk patients, the residual risk of cardiovascular events remains high in patients treated with statins. In a meta-analysis of 26 statin trials by the Cholesterol Treatment Trialists (CTT) Collaborators, use of high-dose statin therapy was associated with a 16% further reduction in major vascular events including mortality as compared to moderate dose statins.

Unfortunately, there remains close to an 70-80% residual risk for clinical events in these optimally LDL-C treated patients. Beyond LDL-C, lipid abnormalities involving low HDL-C and elevated triglycerides (TG) are also associated with increased risk for cardiovascular events.

The Framingham Offspring Study showed that an approximately 1% increase in HDL-C resulted in a roughly 1% reduction in coronary heart disease risk. A meta-analysis from the Emerging Risk Factors Collaboration of 68 studies including 302,430 people free of cardiac disease at baseline showed that elevated TG were associated with acute cardiac events and strokes. Given the residual risk observed with statin therapy and increased risk seen in patients with elevated TG and low HDL-C, alternative lipid lowering therapies including niacin, fibrates, and fish oil have been actively investigated to target these additional lipid abnormalities.

It is now widely believed that elevations in serum triglyceride levels reflect increases in serum remnant lipoprotein levels. The primary lipoprotein secreted by the liver is very low-density lipoprotein (VLDL), a lipoprotein that is highly enriched with triglyceride. VLDL particles undergo progressive lipolysis by lipoprotein lipase with the liberation of free fatty acid, an oxidizable substrate utilized by most visceral organs. As the triglyceride mass is removed, the VLDL is sequentially converted to intermediate-density lipoprotein (IDL) and then LDL. Remnant lipoproteins include smaller VLDLs and IDL. In patients with hypertriglyceridemia, these lipoproteins are elevated due to varying levels of lipoprotein lipase deficiency (both genetic and acquired) and impaired clearance. A number of studies have demonstrated that remnant lipoproteins are atherogenic and correlate with increased risk for cardiovascular events.

In this section, we will evaluate the efficacy of using adjuvant therapy for (1) incremental LDL-C reduction, and (2) treating patients with low HDL-C and high triglycerides. An important distinction has to be drawn at the outset. While no current guideline in the world advocates raising HDL-C as a therapeutic intervention, there is evidence from subgroup analyses that patients experience incremental benefit from adjuvant therapy when both HDL-C is low and triglycerides are high per se.

INCREMENTAL LDL-C LOWERING

Clinical efficacy of ezetimibe

Interest in ezetimibe therapy was greatly diminished following the negative results of the ENHANCE trial. However, the study was deeply flawed in design. The subsequent Stop Atherosclerosis in Native Diabetics Study (SANDS) trial unequivocally demonstrated that the addition of ezetimibe to low-dose simvastatin reduced the progression of carotid intima media thickness as well as high-dose simvastatin therapy. In the PRECISE-IVUS study, the addition of ezetimibe to high-dose atorvastatin increased the magnitude of coronary target atherosclerotic lesion regression in proportion to the magnitude of LDL-C reduction.

In the IMPROVE-IT trial, the combination of ezetimibe with simvastatin provided incremental risk reduction when compared to simvastatin monotherapy. Risk for nonfatal myocardial infarction and ischemic stroke were reduced by 13% and 21%, respectively. Mean attained LDL-C levels were 69 and 53 mg/dl in the monotherapy and combination treatment arms, respectively. In a patient with mixed dyslipidemia, if LDL-C is still not adequately reduced per guidelines or the health care provider’s judgment, then either intensification of statin therapy or the addition of ezetimibe should be the first therapeutic change instituted.

Clinical efficacy of niacin

Treatment with niacin as monotherapy or in combination with other lipid altering therapies, such as statins, has shown vascular and clinical benefits. In the Coronary Drug Project (CDP), monotherapy with niacin in men with a history of a myocardial infarction resulted in a significant 27% reduction in nonfatal myocardial infarction and a 24% reduction in risk for stroke as compared to a placebo.

A 15-year follow-up study of the CDP showed a significant mortality benefit in subjects that were initially randomized to niacin therapy. The vascular benefits of combination therapy with niacin was documented in the Familial Atherosclerosis Treatment Study (FATS), which randomized men to combination therapy with statin plus bile acid binding resin (BABR) (colestipol), niacin plus BABR, or standard therapy which consisted mainly of lifestyle modification and on lipid-modifying therapy. After 2½ years, combination therapy including niacin plus BABR induced 0.7% regression in coronary atherosclerosis by quantitative coronary angiography while the usual care group had a significant 2.1% progression of coronary disease.

In addition, there was a significant 73% reduction in clinical events observed in both combination treatment groups as compared to standard therapy. The vascular benefit of niacin therapy was confirmed in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER-2) evaluating the effects of statin alone versus statin plus extended release niacin on carotid intima-media thickness (CIMT). After 1 year of therapy, CIMT increased by 0.044 mm in the statin only group while the statin plus niacin group had no progression of carotid disease. Similarly, the Armed Forces Regression Study (AFREGS) showed a significant regression of coronary atherosclerosis in patients with atherosclerotic disease randomized to triple therapy with niacin, gemfibrozil, and BABR as compared to progression seen in the control group.

The recent Athero-thrombosis Intervention in Metabolic Syndrome with low-HDL-C/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) study was a large trial of 3,414 subjects designed to test the efficacy of niacin plus statin versus statin only therapy on clinical cardiovascular endpoints. The study was stopped prematurely due to futility to reach a significant difference in events between the two interventions.

Unfortunately, several methodological issues exist with AIM-HIGH that may explain the negative findings. While the study was powered to detect a 25% difference in clinical events between the treatment groups, both groups were on optimal medical therapy with very low baseline LDL-C of 71 mg/dL, and non-HDL-C (defined as total cholesterol minus HDL-C, a measure of total atherogenic lipoprotein burden in serum) of 106 mg/dL, and lipoprotein B of 80 mg/dL.

Also, the statin only group also saw an increase in HDL-C, and the on treatment difference in HDL-C was only 4 mg/dL between the study groups. Given these similar lipid profiles and early termination of the study, the trial was not powered to prove the benefit of adding niacin on a background of statin therapy. However, in a post hoc analysis of the subgroup of patients with baseline triglyceride > 200 mg/dL and HDL-C < 32 mg/dL, niacin adjuvant therapy was associated with a significant 37% relative risk reduction in acute cardiovascular events. The latter analysis suggests benefit in the very group that physicians often targeted for treatment with niacin. The Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS-2 THRIVE) was a study of over 25,000 subjects with atherosclerotic disease on a background of statin therapy randomized to extended release niacin plus laropiprant, a prostaglandin antagonist to minimize flushing, or placebo. In this trial, baseline LDL-C was 63 mg/dl, HDL-C 44 mg/dl, and triglycerides 124 mg/dl. This is not the type of patient for whom niacin therapy would be prescribed. Understandably, the study was negative.

Clinical efficacy of fibrates

While randomized trial data have been variable, treatment using fibrates—including gemfibrozil and fenofibrate—has been documented to lower cardiovascular events in particular subsets of subjects with mixed dyslipidemia. In the Helsinki Heart Study (HHS), treatment with gemfibrozil in 4,081 men free of cardiac disease resulted in a 34% reduction in cardiovascular events as compared to a placebo.

In the HHS, among men with high triglycerides and low HDL-C, gemfibrozil therapy was associated with a 71% relative reduction in cardiac events. The benefit of gemfibrozil therapy versus a placebo was confirmed in the Veterans Affairs-High Density Lipoprotein Intervention Trial (VA-HIT), which randomized men with vascular disease and low HDL-C.

Gemfibrozil therapy resulted in a 24% reduction in cardiac events. Among diabetic subjects in VA-HIT, the risk for the primary composite endpoint decreased by 32%. Unlike gemfibrozil, fenofibrate therapy has failed to show a significant reduction in the primary endpoint of cardiac events in subjects with diabetes in the Fenofibrate Intervention and Event Lowering Diabetes (FIELD) trial.

However, post-hoc analysis of the FIELD study did show a 27% significant reduction in cardiac events in a subgroup of subjects with low HDL-C and elevated TG. A similar finding was noted in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, where treatment with combination therapy of fenofibrate plus statin overall did not show a reduction in the primary endpoint as compared to statin alone.

However, there was a close to statistically significant reduction in cardiac events (P = 0.06) in subjects with low HDL-C <34 mg/dL and TG >204 mg/dL. Therefore, the aggregate data from these trials suggest a possible benefit of fibrate therapy for subjects with mixed dyslipidemia. Of significant importance in both FIELD and ACCORD is the observation that fenofibrate reduced the incidence of proliferative retinopathy significantly in both studies.

Clinical efficacy of fish oil

One of the first studies to show the clinical benefit of omega-3 fatty acids or fish oil was the Diet and Reinfarction Trial (DART) that randomized 2,033 post-MI subjects to a diet that was high in fiber, polyunsaturated fats, or fish oil. After 2 years, the fish oil group had a 29% reduction in all-cause mortality while the other diets had no changes in clinical events.

A similar benefit was observed in the Gruppo Italiano per lo Studo della Sopravvivenza nell’Infarcto Miocardico-Prevenzione (GISSI-Prevenzione) trial where 11,324 post-MI subjects were randomized to 1 g/day of fish oil or a placebo. There was a significant 25% reduction in cardiovascular death in the fish oil group. As a follow-up to the GISSI-Prevenzione trial, the GISSI-Heart Failure trial showed a significant 9% reduction in death or hospitalization for cardiac reasons in heart failure subjects randomized to fish oil supplementation.

In the JELIS trial, the addition of purified eicosapentaenoic acid (EPA) to statin therapy induced a 19% relative risk reduction in the primary cardiovascular endpoint. However, in patients on statin therapy with triglycerides >150 mg/dL and HDL-C <40 mg/dL, the addition of EPA was associated with a significant 53% reduction in the primary endpoint.

Differences between drugs within the class

Ezetimibe

Ezetimibe is available as a single formulation (Zetia). It is also now available in generic form.

Niacin

Niacin is currently available in three preparations: immediate release (IR), sustained release (SR), and extended release (ER). IR niacin, used in FATS and AFREGS trials, is administered 2 to 3 times per day; with its rapid absorption and metabolism, it is associated with a high incidence of adverse events, particularly flushing.

SR niacin releases the drug slowly over time and therefore results in less immediate side effects as compared to IR niacin. The metabolites of SR niacin through are present for a longer period of time and increases susceptibility to hepatotoxicity. SR niacin is available over-the-counter as a dietary supplement.

ER niacin, used in ARBITER-2, is available by prescription and has been shown to have a better tolerability profile as compared to IR or SR niacin. It has a metabolism rate in between IR and SR niacin, and therefore, has a potential to have less risk for acute side effects than IR niacin and less delayed hepatotoxicity injury than SR niacin.

Clinical comparative trials of different niacin formulations have shown significant reductions in LDL-C and TG, and increases in HDL-C. SR niacin though has been shown to have less HDL-C raising effect than IR niacin, but a greater risk for elevations in liver function tests. ER niacin has a similar HDL-C raising effect as IR niacin but with less flushing.

Fibrates

The currently available fibrates include gemfibrozil, fenofibrate, and fenofibric acid. Gemfibrozil, unlike fenofibrate or fenofibric acid, can inhibit the glucuronidation of statins, resulting in reduced elimination and increased risk for statin-related adverse events, especially myopathy and rhabdomyolysis. Neither fenofibrate nor fenofibric acid inhibit the glucuronosyltransferase involved in statin metabolism. Therefore, current guidelines recommend combinations of fenofibrate or fenofibric acid with statins when treating mixed dyslipidemia. Unlike fenofibrate and gemfibrozil, fenofibric acid does not require hepatic first pass metabolism to become an active metabolite once it dissociates in the intestine.

Fish oil

Consumption of enriched fish oil or omega-3 polyunsaturated fatty acids can occur in the form of over-the-counter fish oil supplements or prescription concentrated omega-3 fatty acid formulations. The cardiac benefiting ingredients in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), vary in concentrations depending upon the type of supplementation and can range between 20% seen in some over-the-counter products to as high as 85% seen in prescription Lovaza. Controversy exists in defining the optimal ratio of DHA:EPA and which ingredient has the greater cardiac benefit. Over the counter preparations are not recommended because of their low levels of fish oils and presence of undesirable contaminants.

Administration

Ezetimibe

Ezetimibe is taken orally once daily. It can be taken concomitantly with statins, fenofibrate, and fish oils.

Niacin

Many over-the-counter formulations for immediate release niacin exist. The usual starting dose for IR niacin is 250 mg/day titrated up to 2 to 3 g/day in three divided doses. Sustained and extended release niacin (Niaspan) is administered at an initial dose of 500 mg daily at bedtime, with titration by 500 mg/day every 4 weeks up to 2 g/day depending upon desired response and as tolerated.

Fibrates

Gemfibrozil (Lopid) is dosed 600 mg twice daily 30 minutes before breakfast or dinner. Fenofibrate (Tricor) dosing is initiated at 145 mg/day and lowered to 48 mg/day for patients with creatinine clearance of < 50 mL/min. Fenofibric acid (Trilipix) initial dosing is 135 mg/day and lowered to 45 mg/day for patients with creatinine clearance of < 50 mL/min. For patients with severe renal impairment with creatinine clearance less than or equal to 30 mL/min, fibrates should be avoided.

Fish oil

For treatment of hypertriglyceridemia, omega-3-acid ethyl ester (Lovaza), is dosed 4 g/day as single dose or divided in two doses. One gram of Lovaza contains 375 mg DHA and 465 EPA. Vascepa contains the ethyl ester of EPA. A third prescription grade fish oil is not yet available (Epanova), and is a fish oil-derived mixture of free fatty acids, with at least 850 mg of polyunsaturated fatty acids, including multiple omega-3 fatty acids (EPA and DHA being the most abundant). The ability of Vascepa and Epanova to provide cardiovascular risk reduction in patients on statin therapy and with hypertriglyceridemia is being tested in the REDUCE-IT and STRENGTH trials, respectively. Over-the-counter fish oil supplements have varying DHA and EPA concentrations, ranging from 200 to 900 mg of DHA and EPA.

Pharmacologic action

Ezetimibe

Ezetimibe is a very valuable inhibitor of gastrointestinal cholesterol absorption. It acts at the level of the jejunal brush border and inhibits Nieman Pick C1-like protein. It also inhibits (NPC1L1) within the biliary tree, thereby reducing the reuptake of cholesterol from bile. Ezetimibe is dosed once daily at 10 mg. In addition to decreasing LDL-C by 18-20%, it also decreases non-HDL-C, and modestly decreases triglycerides and negligibly (1-2%) increases HDL-C. On a practical level, it induces a 2-3-fold increase in the percentage of patients able to achieve LDL-C < 70 mg/dL, non-HDL-C < 100 mg/dL, and apoprotein B100 < 80 mg/dL. Ezetimibe undergoes glucuronidation within the enterophepatic circulation and its concomitant use with gemfibrozil should be avoided.

Niacin

Niacin can increase HDL-C by 15% to 40%, lower TG by 20% to 40%, and reduce LDL-C by 10% to 15%. The mechanisms by which niacin induces changes in lipid metabolism are complex and as yet incompletely understood.

Niacin stimulates hepatic production of apo-A1 and HDL-C. Niacin inhibits HDL-C particle uptake and catabolism by hepatocytes. Both of these effects increase circulating levels of HDL-C. Niacin decreases hepatic VLDL and triglyceride secretion by the following mechanisms:

(1) It reduces the flux of fatty acids from visceral adipose tissue to the liver by inhibiting hormone-sensitive lipase. This decreases the amount of fatty acid available for hepatic triglyceride biosynthesis; (2) it decreases triglyceride formation within hepatocytes by inhibiting diacylglycerol-acyltransferase-2, an enzyme that esterifies fatty acid to glycerol; and (3) reduces VLDL-C and LDL-C concentrations by increasing the catabolism of apolipoprotein B.

By reducing serum triglyceride levels, there is less activation of cholesterol ester transfer protein (CETP). When serum triglyceride levels are high, CETP offloads excess triglycerides from VLDL and transfers them into HDL and LDL particles. The triglyceride enriched particles are catabolized by hepatic lipase, which breaks down HDL and decreases LDL particle size and increases LDL particle number.

Fibrates

Fibrates lower TG by 35% to 50%, raise HDL-C by 5% to 20% (depending on baseline triglyceride levels; the higher the triglycerides, the greater the anticipated rise in HDL-C), and have variable effects on LDL-C. The lipid effects of fibrates are mediated by activation and inhibition of genes whose expression is regulated by peroxisome proliferator-activated receptor-alpha (PPAR-alpha), which results in decreased hepatic VLDL secretion, enhanced lipolysis, and removal of TG-enriched lipoproteins, and increased production of apoproteins A-1 and A-2, the two primary apoprotein constituents of HDL particles.

Fish oil

Fish oil lowers TG by 25% to 45% at doses of 4 g/day. Also, fish oil modestly raises HDL-C by 1% to 5% and LDL-C in proportion to the baseline LDL-C but can also lower the LDL particle number. EPA monotherapy reduces triglycerides and is neutral on LDL-C. EPA and DHA are transported from the intestinal tract to the liver via chylomicrons and subsequently released from the liver into the serum in lipoproteins particles and phospholipids, where they can be incorporated into cell membranes.

Changes to cell membranes and regulation of gene transcription by direct binding of omega-3-fatty acids onto a nuclear receptor, such as PPARs, are the hypothesized mechanism of action of EPA and DHA. In addition to their lipid altering affects, fish oil has also been shown to lower blood pressure and resting heart rate, and reduce the risk of cardiac arrhythmias, though this is controversial and as yet unsettled.

Indications and contraindications

Indications

Ezetimibe is indicated to reduce serum levels of LDL-C, non-HDL-C, and apoprotein B. Niacin is indicated for the treatment of hypercholesterolemia or combined hyperlipidemia with low HDL-C. Fibrates are indicated for the treatment of hypertriglyceridemia or combined hyperlipidemia. Fish oil is predominantly indicated for the treatment of hypertriglyceridemia. Treatment with fibrates and fish oil are indicated for the treatment of severe hypertriglyceridemia with TG >500 mg/dL to possibly lower the risk of acute pancreatitis.

Contraindications

Ezetimibe should not be used in combination with gemfibrozil or cyclosporine. It is also contraindicated in patients with severe liver disease. Niacin therapy is contraindicated in patients with severe liver disease and severe gout, and should be used with caution in patients with diabetes, elevated uric acid levels, and peptic ulcer disease. Gemfibrozil should not be used in patients taking concurrent statin therapy. Absolute contraindications for fibrate therapy include severe renal and hepatic disease. Fish oil should be used with caution in patients taking anticoagulants due to the risk of bleeding complications.

Undesirable effects

Ezetimibe

Ezetimibe therapy can be associated with a low risk (<1%) for myalgia and mild elevations in serum transaminase levels.

Niacin

The most common limiting side effect with niacin therapy is flushing. This prostaglandin-mediated side effect appears less common in extended release niacin compared to immediate release niacin and can be reduced by co-administration of aspirin therapy 30 to 60 minutes prior to niacin dosing. Several clinical trials have demonstrated that niacin can increase serum glucose levels particularly in patients with diabetes.

However, minor changes to antidiabetic agents appear to be sufficient to control blood glucose levels. In addition to glucose, niacin can increase serum uric acid levels and precipitate gout attacks. While elevations in liver function tests have been reported, fulminant hepatic failure with niacin is rare.

Fibrates

Myositis has been reported with treatment with fibrates that is increased with concurrent use of statins. This interaction appears isolated to therapy with gemfibrozil and not fenofibrate due to gemfibrozil’s inhibition of statin glucuronidation.

Fish oil

The most common side effect of fish oil is intestinally related burping that appears to be dose related. A risk of bleeding complications has been noted with fish oil intake. Observational studies have shown an increase in clotting time in patients consuming a high fish diet, and there is laboratory evidence suggesting a decrease in levels of thromboxane A2 and platelet coagulation factors.

Randomized controlled trials of fish oil though have not shown a significant increase in bleeding events as compared to controls. Apart from bleeding concerns, treatment with fish oil has shown an increase in LDL-C levels by up to 5%, but appears to decrease the number of atherogenic small dense LDL particles.

Alternative approaches

The PPAR-gamma agonist pioglitazone, used to treat diabetes mellitus, has been shown to alter lipid metabolism with increases in HDL-C and decreases in TG. In the Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study, treatment with pioglitazone as compared to glimepiride for 18 months in subjects with diabetes was associated with a significant increase in HDL-C and less progression of CIMT. Similar lipid and vascular benefits with pioglitazone were noted in the PERISCOPE trial where therapy with pioglitazone for 18 months resulted in an HDL-C increase of 16% and TG decrease of 5.3% and was associated with a significant 0.16% decrease in percent atheroma volume by intravascular ultrasound. In general, only the 15 and 30 mg doses should be used and its use is restricted to diabetic patients.